This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Early identification of African Americans (AA) at risk for hypertension (HTN) may provide an opportunity to prevent progression of the disease. One HTN-related intermediate phenotype of interest is the variable blood pressure (BP) response to changes in salt and'water homeostasis. This salt-sensitivity (SS) to BP may be genetically determined as over 50% of hypertensive AA are NaCI-sensitive and have a greater propensity to develop hypertensive target-organ damage. The -main objective of this project is to characterize physiologic alterations in vascular and cardio-renal function in response to salt intake in genetically susceptible non-hypertensive AA and to assess the potential pathobiological pathways mediating these end-organ responses to salt. Our hypothesis is that a high salt/low potassium diet, typical of AA, inhibits the classic circulating reninangiotensin- aldosterone system (RAAS) but activates the tissue angiotensin-aldosterone system. The local generation of angiotensin and aldosterone within tissue compartments promotes the generation of reactive oxygen species that impairs nitric oxide (NO)-mediated vasodilatory function. It is postulated that this impairment in endothelial function contributes to vascular dysfunction and increased susceptibility to the early development of sub-clinical end-organ dysfunction, by mechanisms additional to the salt-induced rise in BP;However, there have been limited attempts to carefully characterize the effects of salt on BP and downstream targets of the RAAS, circulating markers of oxidative stress as potential determinants of impaired endothelial function in a substantive sample of non-hypertensive AA. We propose careful physiologic experiments that will combine manipulations of angiotensin levels and novel marker of oxidative stress and vascular function in non-HTN AA at risk for end-organ dysfunction. The proposed project will be among the first to systematically define the early influence of variations in salt intake on these specific markers of vascular and cardiac/renal function and to characterize the effect of this response in this unique population-based sample of otherwise healthy subjects.